Acetyl salicylic acid is commonly known by its trade name Aspirin. Aspirin® is a registered trademark of Bayer AG in Germany and more than 80 other countries. Aspirin is an effective non-steroidal analgesic, antipyretic and anti-inflammatory drug and is one of the most widely used medicine around the world. The use of aspirin expands beyond pain relief to life saver as it reduces the risk of heart stroke by preventing the aggregation of blood platelets. The average prescribed dose of aspirin is 0.3-1 g per day, however, large single dose of 10-30 g of aspirin can results to be fatal. Today more than 10 million kilograms of aspirin is produced in US alone per year. The acetyl salicylic acid was first prepared in 1897 by Felix Hoffmann, a German chemist working for Friedrich Bayer & Co in Elberfeld and was marketed in 1899 under the registered trademark of Aspirin®. The first British patent of acetyl salicylic acid was obtained by Otto Bonhoeffer in 1900.
Acetyl salicylic acid is commercially synthesized by Kolbe-Schmidt reaction which is a multi-step process. In this process, phenol is treated with a sodium base generating sodium phenoxide, which is then reacted with carbon dioxide under high temperature (125° C.) and pressure (100 atmosphere) to yield sodium salicylate, which on acidification yields salicylic acid. Salicylic acid is then acetylated with acetic anhydride to prepare acetyl salicylic acid. Existing process of the synthesis of acetyl salicylic acid is an acid catalyzed esterification reaction by the acetylation of the salicylic acid with acetic anhydride using conventional liquid acids, namely, conc. H2SO4 or conc. H3PO4 at the temperature of 80-90° C.

O-acetylation or esterification of salicylic acid with acetic anhydride is carried out using an acid catalyst (D. B. Brown, L. B. Friedman, J. Chem. Educ. 50, 214, 1973) mainly sulfuric acid (D. L. Pavia, G. M. Lampman, G. S. Kriz, Introduction to Organic Laboratory Techniques: A Contemporary Approach; Saunders: Philadelphia, pp 27-30, 1976) and phosphoric acid (J. A. Miller, E. F. Neuzil, Modern Experimental Organic Chemistry; Heath: Lexington, Mass., pp 192-197, 1982; K. L. Williamson, Macroscale and Microscale Organic Experiments, 2nd Ed., Houghton Mifflin, Boston, p 379, 1994; J. Olmsted III, J. Chem. Educ. 75, 10, 1261, 1998) at 80-90° C. The reaction mixture is cooled in ice bath followed by addition of chilled water in the reaction mixture to hydrolyze unreacted acetic anhydride to acetic acid. The reaction mixture is kept for crystallization of acetyl salicylic acid. The crystals are separated by vacuum filtration. These processes have the drawbacks in terms of using corrosive, hazardous mineral acids, which involve post reaction work-up for the disposal of spent acid.
Reference is made to D. Y. Hung et al. in Inter. J. Pharma 153, 25, 1997, who have reported synthesis of acetyl salicylic acid from salicylic acid and acetic anhydride using sulfuric acid at 80° C. and salicylic acid, acetyl chloride and pyridine at 0° C. The process has a drawback in using hazardous acylating agents. Acetyl chloride causes irritation and produces hydrochloric acid during reaction. Pyridine also causes irritation and could also have adverse biological effect. Furthermore, pyridine has to be removed by dissolving the reaction mixture several times in water, which finally goes into waste water effluents.
S. Pandita et al. in J. Chem. Educ. 75, 770, 1998 have reported synthesis of acetyl salicylic acid from salicylic acid and acetyl chloride-pyridine in a cold water bath with 33% yield. Besides showing lower yields, the process also has the drawbacks of using acetyl chloride and pyridine.
Y. Peng et al. in Chem. Educator 5, 144, 2000 have reported the synthesis of acetyl salicylic acid from salicylic acid and acetic anhydride using 12-tungustophosphoric acid as a homogeneous catalyst at room temperature with 57-71% yield. The crude product was treated with sodium bicarbonate until no further bubbles were released. A gum like polymeric byproduct was formed which was removed by vacuum filtration and the filtrate was treated with 2M HCl to adjust the pH to 2. The drawback of the synthesis is the use of water-soluble 12-tungustophosphoric acid, which cannot be recovered and results in acid waste effluent. Furthermore, gummy polymeric by-product formed during the synthesis needs to be removed and the crude product is also required to be purified by the treatment with saturated sodium bicarbonate leading to increase in unit-operation to obtain the final product.
G. A. Mirafzal et al. in J. of Chem. Edu. 77, 3, 356, 2000 have reported the microwave assisted rapid synthesis of acetyl salicylic acid from salicylic acid and acetic anhydride using phosphoric acid as catalyst. Re-crystallization of the product in toluene resulted in a 75% yield of a pure product. This process has serious drawback as the use of corrosive and hazardous phosphoric acid is not appropriate for the use in microwave oven from the safety point of view of reaction system and the operating person, as reactor is a closed system. The separation of residual phosphoric acid from reaction mixture needs water work up and goes into waste water effluent. Toluene is also not a good solvent used for re-crystallization as it releases volatile organic vapors into the atmosphere.
A. K. Bose et al. in Chemtech, 18, 1997 have also reported the synthesis of acetyl salicylic acid from salicylic acid and a slightly more than molar equivalent of acetic anhydride using phosphoric acid as catalyst in domestic microwave oven. The synthesis was then carried out on 500-800 g scale using commercial microwave applicators with 80% yield. This process has serious drawback as the use of corrosive and hazardous phosphoric acid is not appropriate to use in microwave oven from the safety point of view of reaction system and operating person, as reactor is a closed system.
A. K. Bose et al. in Fifth International Electronic Conference on Synthetic Organic Chemistry (ECSOC-5) September 2001 further extended the synthesis of acetyl salicylic acid from salicylic acid and acetic anhydride using phosphoric acid as a catalyst in microwave reactor for 5 minutes by adding 1% magnesium sulfate as an additional microwave energy absorber and for excellent crystal formation of acetyl salicylic acid. The yield of acetyl salicylic acid in these experiments was in the range of 86-97%. The drawback of this process is also the use of corrosive and hazardous phosphoric acid in microwave oven and the resulting acid waste water effluent.
I. Montes et al. in J. of Chem. Edu. 83, 4, 628, 2006 have reported the microwave assisted synthesis of acetyl salicylic acid from salicylic acid and acetic anhydride using different acidic catalysts namely H2SO4, H3PO4, AlCl3, MgBr2.OEt2 and basic catalysts namely CaCO3, NaOAc, NEt3 and dimethylaminopyridine. The yield of the pure acetyl salicylic acid obtained was in the range of 30-77%. However, the drawback of the process is that all the catalysts used for the synthesis are highly corrosive and need to be handled with care in closed system of microwave synthesis. Furthermore, by using an acidic catalyst, an unwanted polymeric by-product is also formed.
Therefore, the existing process for the synthesis of acetyl salicylic acid is beset with serious drawbacks. For example, the use of hazardous mineral acids is not safe from handling point of view, as these are corrosive and irritant; difficult to separate after the reaction and therefore encounters the problem of spent acid disposal. Furthermore, to recover and crystallize the crude acetyl salicylic acid product from the reaction mixture is also a time consuming tedious process and results into low yield of the product. Besides, a brown liquid impurity also appears during re-crystallization of acetyl salicylic acid from water, usually in trace amount but sometimes it is also formed in large quantity, and needs to be removed by filtering the hot aqueous solution and thus making crystallization process tedious and results into acetyl salicylic acid crystals of low purity.
Therefore, methodology to synthesize acetyl salicylic acid to overcome the above mentioned disadvantages employing an eco-friendly and safer catalyst with high yield of acetyl salicylic acid crystals of high purity is needed.